Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
FEBS J. 2010 Nov;277(22):4591-601. doi: 10.1111/j.1742-4658.2010.07888.x.
Many proteins and peptides can form amyloid-like structures both in vivo and in vitro. Although strikingly similar fibrillar structures can be observed across a variety of amino acid sequences, the fibrils formed often exhibit a stunning wealth of polymorphisms at the level of electron or atomic force microscopy. This appears to violate the Anfinsen principle seen for globular proteins, where each protein sequence codes for just one well-defined fold. To a large extent, polymorphism reflects variable packing of a single protofilament structure in the mature fibrils. However, we and others have recently demonstrated that polymorphism can also reflect real structural differences in the molecular packing of the polypeptide chains leading to several possible protofilament structures and diverse mature fibrillar structures. Glucagon has been a particularly useful model system for studying the fibrillogenesis mechanisms that lead to the formation of structural polymorphism, thanks to its single tryptophan residue and the availability of large quantities at pharmaceutical-grade quality. Combinations of structural investigations and seed extension experiments have revealed the reproducible formation of at least five different self-propagating fibril types from subtle variations in growth conditions. These reflect the underlying complexity of the peptide conformational landscape and provide a link to natively disordered proteins, where structure is dictated by context in the form of different binding partners. Here we review some of the latest advances in the study of glucagon fibrillar polymorphism and their implications for mechanisms of fibril formation in general.
许多蛋白质和肽在体内和体外都可以形成类似淀粉样的结构。尽管在各种氨基酸序列中都可以观察到惊人相似的纤维状结构，但在电子或原子力显微镜水平上，形成的纤维通常表现出惊人的丰富多态性。这似乎违反了球状蛋白的 Anfinsen 原则，其中每个蛋白质序列仅编码一种明确的折叠。在很大程度上，多态性反映了成熟纤维中单一原纤维结构的可变包装。然而，我们和其他人最近证明，多态性也可以反映多肽链分子包装中的真实结构差异，从而导致几种可能的原纤维结构和不同的成熟纤维结构。由于其单个色氨酸残基和可获得大量药物级质量的物质，胰高血糖素一直是研究导致结构多态性形成的纤维形成机制的特别有用的模型系统。结构研究和种子延伸实验的组合揭示了至少五种不同的自传播纤维类型的可重复形成，这些纤维类型是由生长条件的细微变化引起的。这些反映了肽构象景观的潜在复杂性，并为天然无序蛋白提供了联系，在天然无序蛋白中，结构由不同结合伴侣形式的上下文决定。在这里，我们回顾了胰高血糖素纤维多态性研究的一些最新进展及其对纤维形成机制的一般意义。
